The goal of this study is to identify novel mechanisms leading to cardioprotection during cancer treatment. In cardiac tissue, both cytotoxic and cytoprotective actions are implicated in the action of tumor necrosis factor alpha (TNFalpha). Although a variety of cancer therapeutic agents have been shown to induce rapid expression of TNFalpha and both types of TNF receptors (p55 and p75) are expressed in cardiomyocytes, the role of this cytokine and its associated receptors in cardiac response to cancer therapy is unknown. The anti-estrogen tamoxifen (TAM) has been shown to have a beneficial effect not only in the reduction of contralateral breast cancer but also to result in a reduced incidence of heart disease in cancer patients. Tamoxifen is generally thought to act as an anti-estrogen in breast cancer to inhibit tumor growth. However, the cardioprotective effect observed in various clinical trials suggests that the mechanism of action of anti-estrogens is complex and cannot be described simply as an estrogen lacking TNF receptors are more sensitive to ADR-induced cardiac injury and that pre-treatment with TAM results in a dose-dependent reduction of the p75 TNF receptor and suppression of TNFalpha-induced mitochondrial injury. These results suggest that low levels of endogenous TNF may be cardioprotective whereas high levels of TNFalpha are cardiotoxic. We hypothesized that 1) endogenous TNFalpha serves a cardioprotective role by rapid activation of the block. Our preliminary data indicate that mutant mice lacking nuclear factor kappa Beta (NFkBeta) with subsequent induction of protective proteins; 2) high levels of TNFalpha cause excessive TNF-receptors mediated-induction of mitochondrial injury; and 3) enhancement of mitochondrial antioxidant capacity improves TAM-induced cardioprotection. The role of TNFalpha and TAM in cardiac injury will be established in animals, isolated mitochondria, and isolated cardiomyocytes. Genetically modified animals will be used to investigate the link between TNF/TAM and mitochondrial antioxidant status in cardioprotection. The proposed studies will provide fundamental information concerning the role of TNF and TAM in cardiac injury. The results should also provide insights into the link between mitochondrial antioxidant status and TAM. The results could lead to the development of selective approaches to improve protection of the heart, thus reducing the toxicity of free radical-associated anti-cancer agents.